The present invention relates to an iontophoresis device suitable for treatments through percutaneous and mucosal applications of drugs.
Recently, there have been developed a variety of dosage forms in the field of pharmaceutical preparations for external use and the development has gradually become a matter of great concern. The reason for this is as follows: The administration of a drug, which may have a local and systemic pharmacological action, through the skin or the mucous membranes has many advantages. For instance, the sustained release effect of the drug can be expected; the rate of the drug-absorption can easily be controlled and any side-effect due to the administration of an excess drug can be prevented; such administration is not greatly influenced by the metabolism due to the first-pass effect in the liver unlike the oral administration and permits the effective use of the drug; and drugs accompanied by, for instance, liver disorders can relatively safely be administered.
However, the normal skin naturally has a protective effect against external stimulations and this makes the absorption and penetration of a drug through the skin relatively difficult. For this reason, in the existing circumstances, a drug is not absorbed in an amount sufficient for ensuring a sufficient desired effect even if the drug is administered in a dosage form for external use.
Moreover, in the administration method, which makes use of absorption routes through biological membranes other than the skin, such as mouth, rectum, oral cavity and nose as well as the sublingual route, it is difficult to penetrate into or transmit through the related biological membrane depending on the kinds of drugs and therefore, there have been known a large number of drugs having low bioavailability. Accordingly, there has been desired for the development of an absorption-promoting method, which can sufficiently enhance the permeability, penetrability and absorbency of a drug against the skin and other biological membranes, can ensure a sufficient pharmacological efficacy of the drug and is substantially free of, for instance, its local and systemic toxicity and is highly useful and safe.
As such absorption-promoting methods, there have recently been known, chemically promoting methods, which make use of absorption-promoting agents; and physically promoting methods in which iontophoresis orphonophoresis is employed. Among these, the iontophoresis method has unexpectedly attracted special interest recently and has been expected as an administration method, which permits the solution of the foregoing problems. The iontophoresis method is one for the administration of a drug by applying a voltage to the skin or a mucous membrane to thus electrically induce the migration of an ionic drug and to in turn administrate the drug through the skin or a mucous membrane.
In general, an iontophoresis device has a structure comprising a combination of a layer for storing a drug therein and electrodes. An effective component in a previously designed amount and, if necessary, a variety of additives for maintaining the drug efficacy are encapsulated into the drug-storing layer for the purpose of maintaining a desired blood concentration of the effective component over a predetermined period of time. In addition, the device is provided with two electrodes, i.e., an anode and a cathode as iontophoresis electrodes and is so designed that these electrodes are arranged on or attached to the skin at a predetermined distance apart from one another and that an electric current generated by a current generator is guided to these electrodes to thus carry out treatments.
The iontophoresis device of this type is, for instance, disclosed in Japanese Un-examined Patent Publication Nos. Sho 62-268569, Hei 2-131779, Hei 3-268769; and Hei 3-45271 and TOKUHYO Nos. Hei 3-504343 and Hei 3-504813.
If a drug (such as physiologically active peptides), which suffers from a problem of the solubility in water, is used in these iontophoresis device, however, the predetermined amount of the drug may be reduced due to the partial decomposition thereof with time. Moreover, if a drug is administered in a high concentration, the drug may be diluted during storing.
If a peptide drug is percutaneously administered by the iontophoresis, it is common that the drug is not maintained in an iso-electric environment, but is kept in an acidic or basic environment. For this reason, the stability of additives, which are incorporated into the device to assist the development of the pharmacological efficacy of the biologically active substance, is greatly influenced by such acidic or basic environment and accordingly, the drug efficacy may be reduced.
Moreover, it has been recognized that in a device, which is designed in such a manner that an electrically conductive layer containing a drug in the form of a solution is directly in contact with the electrodes immediately after the electrical charging, the drug is electrolytically decomposed on the electrode surface during electrically charging the device. Accordingly, it would be doubtful whether the decomposed drug through its internal absorption adversely affects the human body.
There have been proposed a variety of methods for the solution of such a problem. For instance, Japanese Un-Examined Patent Publication No. Sho 63-102768 and U.S. Pat. No. 5,310,404 disclose a method, which comprises the steps of arranging a capsule or a porch enclosing water or an electrolyte solution above the electrode structure and breaking the capsule or porch immediately before the practical use to thus impregnate the drug-support layer therewith. This method is excellent in that the drug can be stored in a stable condition (dry state), but it is still insufficient since it takes a long period of time for uniformly permeating the moisture into the whole drug-support layer and the drug efficacy may be reduced due to the dilution of the drug.
In addition, Japanese Patent No. 2,542,792 discloses a method in which a drug-support layer and an electrode layer containing an electrolyte are separately disposed in distinct compartments, which are hinged to one another and then piling one upon another at the hinged portion to thus activate the device. This method permits the improvement in the long-term stability of a drug, but a release cover is brought into contact with the drug-support portion at the time of activating the device, the drug dissolved may accordingly be adhered to the release cover and any uniform drug content in the pharmaceutical preparation cannot be maintained at all. In addition, any means for activating the device upon application is not sufficiently devised and therefore, the method may include a lot of causes for artificial errors and cannot achieve sufficiently uniform distribution of the drug after the activation of the device. Thus, the device is not practicable.
Moreover, Japanese Un-Examined Patent Publication No. Hei 3-94771 discloses a device, which is so designed that a selective ion-permeable membrane (such as an ion-exchange membrane) is arranged such that the membrane is adjacent to the skin side of a water-support portion thereof, while a drug is dried and adhered to the side of the selective ion-permeable membrane, which is in contact with the living body, to thus prevent any dilution of the drug and to realize the administration of a trace amount of the drug to a local site in a high concentration.
Japanese Un-Examined Patent Publication No. Hei 9-201420 discloses a device for iontophoresis, in which an electrode structure layer, a solvent-support layer and a drug-support layer containing a dried physiologically active substance are put in a layer structure in this order and a water-impermeable separator later is positioned between the solvent-support layer and the drug-support layer. This device is so designed that the solvent-support layer is automatically brought into contact with the drug-support layer by pulling out the separator layer upon activation. This device is quite excellent in that the occurrence of any artificial error is prevented when assembling the device. In this device, however, the solvent-support layer and the drug-support layer are accommodated in the same package, the solubility of the drug may be reduced due to any leakage of the solvent from the solvent-support layer and accordingly, it is difficult to ensure the quality of the device. Moreover, even if it were technically possible to completely prevent the leakage of the solvent, the cost required for the development of such a technique would be very high.
As has been described above, there has not yet been developed any iontophoresis device and any method for operating the device, which can ensure the long-term stability of a drug, can easily and accurately be activated immediately before the practical use thereof and permits the elimination of any artificial error as much as possible.
Accordingly, it is an object of the present invention to provide an iontophoresis device, which can ensure the long-term stability of a drug and can easily be assembled immediately before the application.
The foregoing object of the present invention can be accomplished by providing an iontophoresis device having the following structure. More specifically, the inventors of this invention have conducted various studies to solve the foregoing problems and as a result, have completed the device. The device is so designed that a space is secured between a drug-support and a cover by protecting the drug-support with the cover, which is formed into, for instance, a cup-like shape to thus prevent any migration of a drug solution towards the cover. Thus, in the step for applying a predetermined amount of the drug solution to the drug-support, keeping the drug solution in the support and drying the same, the desired content of the drug in the drug-support can stably be ensured. Moreover, a hole for applying the drug solution can be formed through the cup-like cover to thus permit the practice of a series of steps, i.e., the application of the drug solution to the drug-support, the retention and drying thereof, while the cover is fitted to the drug-support and this also makes the handling of these parts upon the assemblage of the device easy and simple.
In addition, in the iontophoresis device according to the present invention, the drug-support does not directly come in contact with the release cover upon the activation of the device and therefore, any drug re-dissolved is never adhered to the release cover and any reduction of the drug content in the pharmaceutical preparation can be prevented. Moreover, upon practical use, a patient can apply the device to the body without directly putting the hand on the drug-support. Therefore, it is not necessary to fear about any adsorption of the drug on the sebum of the hand, any decomposition of the drug due to the moisture adhered to the hand, or any contamination of the drug portion with the stain, foreign substances adhered to the hand or the like. Moreover, the use of the drug-support permits the achievement of a desired administration area and the quantitative administration of the drug.
Furthermore, the iontophoresis device according to the present invention has a technical configuration described above and therefore, the drug portion and the drug-dissolving portion can separately be stored prior to the operation of the device. For this reason, if a drug whose stability to water is low (for instance, physiologically active peptides), is incorporated into the drug portion, it is not necessary to fear about the decomposition, with time, of the drug due to evaporation of water from the electrode portion provided with a built-in drug-dissolving portion. In addition, it is not needed to use any package for completely preventing any evaporation of water from the electrode and therefore, the device is also improved from the economical standpoint. Such a configuration permits the use of a stability-improving agent for the drug portion such as a drying agent, which cannot be used when the drug portion and the drug-dissolving portion are united, while taking into consideration the influence thereof on the drug-dissolving portion. Accordingly, the long-term stability of the drug can further be improved.
Moreover, the cup portion of the cover for protecting the drug-support has an additional structure for accurately put the drug portion and the drug-dissolving portion on top of each other. In this respect, the term xe2x80x9cadditional structuresxe2x80x9d means, for instance, a hole and a rod to be inserted into the hole, formed at the positions on the drug portion and the drug-dissolving portion, which coincide with one another. The drug-support portion and the drug-dissolving portion can be precisely put on top of each other by positioning of these portions while making use of the additional structure.
In addition, a hole formed on a part of the release cover of the drug-dissolving portion can be joined with the cup portion of the cover for protecting the drug-support and the drug-dissolving portion and the drug-support can be put on top of one another in a correct correlation by folding the release cover.
Further, a convex or concave frame is arranged at the periphery of the drug-dissolving portion and thus the drug-dissolving portion and the drug portion can be put on top of one another in a correct relation by incorporating the cup portion of the drug portion into the frame.
Moreover, the peripheral portion of the drug portion is formed into a concave or convex shape, while the corresponding portion on the drug-dissolving portion is likewise formed into a convex or concave shape. Thus, the drug portion and the drug-dissolving portion can be put on top of each other in a correct relation by combining these concave and convex portions.
Furthermore, the interior of the cup of the protective cover on the drug portion is formed into a shape such that the drug-support can be maintained there in and thus, the drug portion and the drug-dissolving portion can be put on top of each other in a correct relation by pressing the cup portion from the top thereof.
Moreover, the foregoing drug portion may be in the form of a drug unit, which comprises a drug-support for holding a drug and a cover arranged on at least one side of the drug-support while keeping the cover and the drug-support apart from one another. The drug unit and the drug-dissolving portion can be put on top of one another in a correct relation by forming a member for positioning at the periphery of the drug unit. In this respect, the cover of the drug unit has, for instance, a cup-like shape and the cup-like cover is provided with an opening for applying the drug.
In addition, the present invention also provide a kit for an iontophoresis device, which comprises an electrode portion provided with a drug-dissolving portion, a drug-support for holding a drug and a cover arranged on at least one side of the drug-support while keeping the cover and the drug-support apart from one another, the drug portion and the electrode portion being accommodated in separate packages. These electrode and drug portions are provided with means for positioning respectively, for putting them on top of one another.
As has been described above, the iontophoresis device according to the present invention permits the easy and correct activation of the device when practically using the same, thus permits any artificial error as low as possible and also permits the correct supply of moisture, to the drug-supply, required for re-dissolution of the drug.